Diacyl-substituted guanidines, a process for their preparation, their use as medicament or diagnostic aid, and medicament containing them.
The invention relates to diacyl-substituted guanidines of the formula I 
in which:
X(1) and X(2) are 
T1 is zero, 1, 2, 3 or 4,
R(A) and R(B) are, independently, hydrogen, F, Cl, Hr, I, CN, OR(106), (C1-C8)-alkyl, (C3-C8)-cycloalkyl, Ozk(CH2)zlCzmF2zm+1, NR(107)R(108), phenyl or benzyl,
xe2x80x83where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(109)R(110),
R(109) and R(110) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
zl is zero, 1, 2, 3 or 4,
zk is zero or 1,
zm is 1, 2, 3, 4, 5, 6, 7 or 8,
R(106) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8)-cycloalkyl, phenyl or benzyl,
xe2x80x83where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(111)R(112),
R(111) and R(112) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
R(107) and R(108) are, independently of each other, defined as R(106), or
R(107) and R(108) are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Cxe2x80x94CH3 or N-benzyl,
or
X(1) and X.(2) are 
T2a and T2b are, independently of each other, zero, 1 or 2, where the double bond can have the E or Z configuration;
or
X(1) and X(2) are 
T3 is zero, 1 or 2,
U, YY and 2 are, independently of each other,
C or N, where U, YY and Z can carry the following number of substituents:
R(D) is hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl,
R(U2), R(U2), R(Y1), R(Y2), R(Z1) and R(Z2) are, independently of each other, hydrogen, F, Cl, Br, I, CN, OR(114), (C1-C8)-alkyl, (C3-C8)-cycloalkyl, Ozka(CH2)zlaCzmaF2zma+1,
NR(115)R(116), phenyl or benzyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(117)R(118),
R(117) and R(118) being hydrogen, (C1-C4)-alkyl or (C1-C4) perfluoroalkyl,
zka is zero or 1,
zla is zero, 1, 2, 3 or 4,
zma is 1, 2, 3, 4, 5, 6, 7 or 8,
R(114) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8)-cycloalkyl, phenyl or benzyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(119)R(120),
R(119) and R(120) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
R(115) and R(116) are, independently of each other, defined as R(114), or
R(115) and R(116) are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Cxe2x80x94CH3 or N-benzyl,
where, however, the constitution II is nitrogen (N), YY is nitrogen (N) and Z is carbon (C) is excepted,
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
hydrogen, F, Cl, Br, I, xe2x80x94Cxe2x89xa1N, Xzoaxe2x80x94(CH2)zpaxe2x80x94(CzqaF2zqa+1), R(110a)xe2x80x94SOzbm, R(110b)R(110c)Nxe2x80x94CO, R(111a)xe2x80x94COxe2x80x94 or R(112a)R(113a)Nxe2x80x94SO2xe2x80x94, where the perfluoroalkyl group is straightchain or branched,
X is hydrogen, S or NR(114a),
zoa is zero or 1, R(114a) being H or (C1-C3)-alkyl,
zbm is zero, 1 or 2,
zpa is zero, 1, 2, 3 or 4,
zqa is 1, 2, 3, 4, 5, 6, 7 or 8,
R(110a), R(110b), R(111a) and R(112a) are, independently, (C1-C8)-alkyl, (C3-C8)-alkenyl, xe2x80x94CznH2znxe2x80x94R(115a) or (C1-C8)-perfluoroalkyl,
zn is zero, 1, 2, 3 or 4,
R(1115a) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, CI, CF3, methyl, methoxy and NR(116a)R(117a),
R(116a) and R(117a) being hydrogen, (C1-C4)-perfluoroalkyl or (C1-C4)-alkyl,
xe2x80x83or
R(110b), R(111a) and R(112a) are also hydrogen,
R(110c) and R(113a) are, independently, hydrogen, (C1-C4)-perfluoroalkyl or (C1-C4)-alkyl,
xe2x80x83or
R(110b) and R(110c) and also R(112a) and R(113a) are together 4 or 5 methylene groups, of which one CH2 group can be replaced by oxygen, sulfur, NH, Cxe2x80x94CH3 or N-benzyl,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
(C1-C8)-alkyl, xe2x80x94CzH2zalR(118a) or (C3-C8)-alkenyl,
zal is zero, 1, 2, 3 or 4,
R(118a) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(119a)R(119b),
R(119a) and R(119b) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other, (C1-C9)-heteroaryl which is linked via C or N and which is unsubstituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other, xe2x80x94Cxe2x89xa1Cxe2x80x94R(193),
R(193) is phenyl which is not substituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(194)R(195),
R(194) and R(195) being hydrogen or CH3,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
-Y-para-C6h4xe2x80x94(CO)zhxe2x80x94(CHOH)zixe2x80x94(CH2)zjxe2x80x94(CHOH)zkxe2x80x94R(123)
-Y-meta-C6h4xe2x80x94(CO)zadxe2x80x94(CHOH)zaexe2x80x94(CH2)zafxe2x80x94(CHOH)zagxe2x80x94R(124)
xe2x80x83or
-Y-ortho-C6H4xe2x80x94(CO)zahxe2x80x94(CHOH)zaoxe2x80x94(CH2)zapxe2x80x94(CHOH)zakxe2x80x94R(125),
Y is oxygen, xe2x80x94Sxe2x80x94 or xe2x80x94NR(122d)xe2x80x94,
zh, zad and zah are, independently, zero or 1,
zi, zj, zk, zae, zaf, zag, zao, zap and zak are, independently, zero, 1, 2, 3 or 4,
where, however, in each case, zh, zi and zk are not simultaneously zero, zad, zae and zag are not simultaneously zero and zah, zao and zak are not simultaneously zero,
R(123), R(124) R(125) and R(122d) are, independently, hydrogen or (C1-C3)-alkyl,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
SR(129), xe2x80x94OR(130), xe2x80x94NR(131)R(132) or xe2x80x94CR(133)xe2x80x94R(134)R(135),
R(129), R(130), R(131) and R(133), are, independently,
xe2x80x94CzabH2zabxe2x80x94(C1-C9)-heteroaryl which is unsubstituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino,
zab is zero, 1 or 2,
R(132), R(134) and R(135) are, independently of each other, defined as R(129), or hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
-W-para-(C6h4)xe2x80x94R(196), -W-meta-(C6h4)xe2x80x94R(197) or -W-ortho-(C6h4)xe2x80x94R(198),
R(196), R(197) and R(198) are, independently,
(C1-C9)-heteroaryl which is linked via C or N and which is unsubstituted or is substituted by 1 to 3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino; methylamino, dimethylamino and benzyl,
W is oxygen, S or NR(136)xe2x80x94,
R(136) being hydrogen or (C1-C4)-alkyl,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
R(146)X(1a)xe2x80x94,
X(1a) is oxygen, S, NR(147), (Dxe2x95x90O)Axe2x80x94 or
M is oxygen or sulfur,
A is oxygen or NR(150), and
D is C or SO,
R(146) is (C1-C8)-alkyl, (C3-C8)-alkenyl,
(CH2)zbzCzdzF2zdz+1 or xe2x80x94CzxaH2zxaxe2x80x94R(151),
zbz is zero or 1,
zdz is 1, 2, 3, 4, 5, 6 or 7,
zxa is zero, 1, 2, 3 or 4,
R(151) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatic radicals are not substituted or are substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy and NR(152)R(153),
R(152) and R(153) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
R(147), R(148) and R(150) are, independently, hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
R(149) is defined as R(146),
xe2x80x83or
R(146) and R(147), or R(146) and R(148), respectively, are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, sulfur, NH, Cxe2x80x94CH3 or N-benzyl, where A and N(*) are bonded to the phenyl nucleus of the alkanoyl parent substance,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
xe2x80x94SR(164), xe2x80x94OR(165), xe2x80x94NHR(166), xe2x80x94NR(167)R(168), xe2x80x94CH R(169)R(170),
xe2x80x94CR(154)R(155)OH, xe2x80x94Cxe2x89xa1CR(156), xe2x80x94CR(158)xe2x95x90CR(157) or xe2x80x94[CR(159)R(260)]zuxe2x80x94(Cxe2x95x90O)xe2x80x94[CR(161)R(162)]zvxe2x80x94
R(163),
R(164), R(165), R(166), R(157) and R(169) are identical or different and are xe2x80x94(CH2)zyxe2x80x94(CHOH)zzxe2x80x94(CH2)zaaxe2x80x94(CHOH)ztxe2x80x94R(171) or xe2x80x94(CH2)zabxe2x80x94Oxe2x80x94(CH2-CH20)zacxe2x80x94R(172),
R(171) and R(172) being hydrogen or methyl,
zu is 1, 2, 3 or 4,
zv is zero, 1, 2, 3 or 4,
zy, zz, zaa, zab and zac are identical or different and are zero, 1, 2, 3 or 4,
zt is 1, 2, 3 or 4,
R(168), R(170), R(154) and R(155) are identical or different and are hydrogen or (C1-C6)-alkyl,
xe2x80x83or
R(169) and R(170), or R(154) and R(155), respectively, are, together with the carbon atom carrying them, a (C3-C8)-cycloalkyl,
R(163) is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or xe2x80x94CzebH2zeb R(173)
zeb is zero, 1, 2, 3 or 4,
R(156), R(157) and R(173) are, independently, phenyl which is unsubstituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy and NR(174)R(175),
R(174) and R(175) being hydrogen or (C1-C4)-alkyl,
xe2x80x83or
R(156), R(157) and R(173) are, independently, (C1-C9)-heteroaryl which is unsubstituted or is substituted as phenyl,
R(158), R(159), R(160), R(161) and R(162) are hydrogen or methyl,
or
R(101), R(102), R(103), R(104) and R(205) are, independently of each other, R(176)xe2x80x94NHxe2x80x94SO2xe2x80x94,
R(175) is R(177)R(178)Nxe2x80x94(Cxe2x95x90Yxe2x80x2)xe2x80x94,
Yxe2x80x2 is oxygen, S or Nxe2x80x94R(179),
R(177) and R(178) are identical or different and are hydrogen, (C1-C8)-alkyl, (C3-C6)-alkenyl or xe2x80x94CzfaH2zfaxe2x80x94R(180),
zfa is zero, 1, 2, 3 or 4,
R(180) is (C5-C7)-cycloalkyl or phenyl which is unsubstituted or substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methoxy or (C1-C4)-alkyl,
xe2x80x83or
R(177) and R(178) are together 4 or 5 methylene groups of which one C82 group can be replaced by oxygen, sulfur, NH, Cxe2x80x94CH3 or N-benzyl,
R(179) is defined as R(177) or is amidine,
or
R(101), R(102), R(103), R(104) and R(105) are, independently of each other,
NR(184a)R(185), OR(184b), SR(184c) or xe2x80x94Cznxxe2x80x94R(184d),
znx is zero, 1, 2, 3 or 4,
R(184d) is (C3-C7)-cycloalkyl or phenyl which is not substituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy and NR(116k)R(117k),
R(116k) and R(117k) being hydrogen or (C1-C4)-alkyl,
R(184a), R(184b), R(184c) and R(185) are, independently of each other,
hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl or (CH2)zaoxe2x80x94R(184g),
zao is zero, 1, 2, 3 or 4,
184g is (C3-C7)-cycloalkyl or phenyl which is not substituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy and NR(184u)R(184v),
R(184u) and R(184v) being
xe2x80x83hydrogen or (C1-C4)-alkyl,
xe2x80x83or
R(184a) and R(185) are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, sulfur, NH, Cxe2x80x94CH3 or N-benzyl,
and also pharmaceutically tolerated salts thereof,
where, however, the following compounds are excepted: 
and
where, additionally, the compounds are excepted in which the radicals R(1) to R(5) are combined as follows:
Compounds of the formula Y are preferred in which X(1) is the same as X(2) and in which the other substituents are as defined above.
Compounds of the formula I are particularly preferred in which:
X(1) and X(2) are 
T1 is zero or 2,
R(A) and R(B) are, independently, hydrogen, F, Cl, CN, OR(106), (C1-C4)-alkyl, (C5-C6)-cycloalkyl, CF3 or NR(107)R(108),
R(106) is hydrogen, (C1-C4)-alkyl, CF3, phenyl or benzyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(111)R(112),
R(111) and R(112) being hydrogen, CH3 or CF3,
R(107) and R(108) are, independently of each other, defined as R(106), or
R(107) and R(108) are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Cxe2x80x94CH3 or N-benzyl,
or
X(1) is 
where the double bond can be in the E or Z configuration,
or
X(1) is 
U, YY and Z are, independently of each other, C or N; with, however, the restriction that only one of the positions U, YY and Z can be nitrogen;
where
U, YY and Z can carry the following number of substituents:
R(D) is hydrogen,
R(U1), R(U2), R(Y1), R(Y2), R(Z1) and R(Z2) are, independently of each other,
hydrogen, F, Cl, CN, OR(114), CH3, CF3 or NR(115)R(116),
R(114) is hydrogen, (C1-C4)-alkyl CF3, phenyl or benzyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(119)R(120), R(119) and R(120) being hydrogen, CH3 or CF3,
R(115) and R(116) are, independently of each other, defined as R(114), or
R(115) and R(116) are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl,
R(101) is hydrogen, F, Cl, CH3, OH, NH2 or CF3,
R(102) is hydrogen, F, Cl, Hr, xe2x80x94Cxe2x89xa1N, xe2x80x94CzqaF2zqaCF3, R(110a)xe2x80x94SO2, R(110b)R(110c)Nxe2x80x94COxe2x80x94, R(111a)xe2x80x94COxe2x80x94 or R(112 a)R(113a) Nxe2x80x94SO2xe2x80x94,
R(110a), R(110b), R(111a) and R(112a) are, independently, (C1-C4)-alkyl, (C3-C4)-alkenyl, xe2x80x94CznH2znxe2x80x94R(115a) or CF3,
zn is zero or 1,
zqa is zero, 1, 2, 3, 4 or 5,
R(115a) is (C3-C6)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy and NR(116a)R(117a),
R(116a) and R(117a)
xe2x80x83being hydrogen or methyl, or
R(110b), R(111a) and R(112a) are also hydrogen,
R(110c) and R(113a) are, independently, hydrogen or methyl,
R(103) is xe2x80x94Y-para-C6H4xe2x80x94(CO)zhxe2x80x94(CHOH)zixe2x80x94(CH2)zjxe2x80x94(CHOH)zkxe2x80x94R(123), xe2x80x94Y-meta-C6H4xe2x80x94(CO)zadxe2x80x94(CHOH)zaexe2x80x94(CH2)zafxe2x80x94(CHOH)zagxe2x80x94R(124) or xe2x80x94Y-ortho-C6H4xe2x80x94(CO)zahxe2x80x94(CHOH)zaoxe2x80x94(CH2)zapxe2x80x94(CHOH)zakxe2x80x94R(125),
Y is oxygen, S or xe2x80x94NR(83),
R(123), R(124), R(125) and R(83) are, independently, hydrogen or methyl,
zh, zad and zah are, independently, zero or 1,
zi, zk, zae, zag, zao and zak are, independently, zero, 1, 2 or 3,
zj, zaf and zap are, independently, zero or 1,
where, however, in each case, zh, zi and zk are not simultaneously zero, zad, zae and zag are not simultaneously zero and zah, zao and zak are not simultaneously zero,
or
R(103) is hydrogen, F, Cl, Br, CN, (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl or xe2x80x94CzalH2zalR(118a),
zal is zero, 1 or 2,
R(118a) is (C3-C6)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(119a) and R(119b),
R(119a) and R(119b) being hydrogen or CH3,
or
R(103) is (C1-C9)-heteroaryl which is linked via C or N and which is unsubstituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino,
or
R(103) is -W-para-(C6H4)xe2x80x94R(196), -W-meta-(C6H4)xe2x80x94R(197) or -W-ortho-(C6H4)xe2x80x94R(198),
R(196), R(197) and R(198) are, independently, pyrrolyl, imidazolyl, pyrazolyl or pyridyl which in each case is unsubstituted or substituted by 1 to 2 radicals selected from the group consisting of F, Cl, CF3, CH3, methoxy, dimethylamino and benzyl,
W is oxygen, xe2x80x94Sxe2x80x94 or NR(136)xe2x80x94,
R(136) being hydrogen or methyl,
or
R(103) is xe2x80x94SR(129), xe2x80x94OR(130), xe2x80x94NR(131)R(132) or xe2x80x94CR(133)R(134)R(135),
R(129), R(130), R(131) and R(133) are, independently of each other,
xe2x80x94CzabH2zabxe2x80x94(C1-C9)-heteroaryl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino,
zab is zero or 1,
R(132), R(134) and R(135) are, independently of each other, hydrogen or CH3,
or
R(103) is R(110a)xe2x80x94SO2 or R(112a)R(113a)Nxe2x80x94SO2xe2x80x94,
R(110a) is (C1-C4)-alkyl, CF3, (C3-C4)-alkenyl or xe2x80x94CznH2znxe2x80x94
R(115a),
zn is zero or 1,
R(115a) is (C3-C6)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(116a)R(117a),
R(116a) and R(117a) being hydrogen or CH3,
R(112a) is hydrogen, (C1-C4)-alkyl, CF3, (C3-C4)-alkenyl or xe2x80x94CzaH2zaxe2x80x94R(115a),
za is zero or 1,
R(115a) is (C3-C6-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(116a)R(117a),
R(116a) and R(117a) being hydrogen or CH3,
R(113a) is hydrogen or CH3,
xe2x80x83or
R(112a) and R(113a) are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl,
or
R(103) is R(146)X(1a)xe2x80x94,
X(1a) is oxygen, S, NR(147), (Cxe2x95x90O)Axe2x80x94 or NR(148)Cxe2x95x90MN(*)R(149)xe2x80x94,
M is oxygen, and
A is oxygen or NR(150),
R(146) and R(147) are, independently, hydrogen, (C1-C6)-alkyl, (C3-C4)-alkenyl, (CH2)zbzCzdzF2zdz+1 or CzxaH2zxaxe2x80x94R(151),
zbz is zero or 1,
zdz is 1, 2, 3, 4, 5, 6 or 7,
zxa is zero or 1,
R(151) is (C3-C6)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy or NR(152)R(153),
R(152) and R(153) being hydrogen or CH3,
R(148) is hydrogen or (C1-C4)-alkyl,
R(149) is defined as R(146), or
R(146) and R(147), or R(146) and R(148), respectively, are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl, where A and N(*) are bonded to the phenyl nucleus of the benzoylguanidine parent substance,
or
R(103) is xe2x80x94SR(164), xe2x80x94OR(165), xe2x80x94NHR(166), xe2x80x94NR(167)R(168), xe2x80x94CHR(169)R(170), xe2x80x94[CR(154)R(155)OH], xe2x80x94Cxe2x89xa1CR(156), xe2x80x94CR(158)xe2x95x90CR(157) or xe2x80x94[CR(159)R(160a)]zuxe2x80x94(CO)xe2x80x94[CR(161)R(162)]zvxe2x80x94R(163), R(164), R(165), R(166), R(167) and R(169) are identical or different and are xe2x80x94(CH2)zyxe2x80x94(CHOH)zzxe2x80x94(CH2)zaaxe2x80x94(CHOH)ztxe2x80x94R(171) or xe2x80x94(CH2)zabxe2x80x94Oxe2x80x94(CH2xe2x80x94CH2O)zacxe2x80x94R(172),
R(171) and R(172) are hydrogen or methyl,
zu is 1 or 2,
zv is zero, 1 or 2, zy, zz, zaa, zab and zac are identical or different and are zero, 1 or 2,
zt is 1, 2 or 3,
R(168), R(170), R(154) and R(155) are identical or different and are hydrogen or methyl,
xe2x80x83or
R(169) and R(170), or R(154) and R(155), respectively, together with the carbon atom carrying them, are a (C3-C6)-cycloalkyl,
R(163) is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or xe2x80x94CzebH2zebxe2x80x94R(173),
zeb is zero, 1 or 2.
R(156), R(157) and R(173) are, independently of each other, phenyl which is unsubstituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(174)R(175),
R(174) and R(175) being hydrogen or CH3,
xe2x80x83or
R(156), R(157) and R(173) are, independently of each other,
(C1-C9)-heteroaryl which is unsubstituted or is substituted as phenyl,
R(158), R(159), R(160), R(161) and R(162) are hydrogen or methyl,
or
R(103) is R(176)xe2x80x94NHxe2x80x94SO2xe2x80x94,
R(176) is R(177)R(178)Nxe2x80x94(Cxe2x95x90Yxe2x80x2)xe2x80x94,
Yxe2x80x2 is oxygen, S or Nxe2x80x94R(179),
R(177) and R(178) are identical or different and are hydrogen, (C1-C4)-alkyl, (C3-C4)-alkenyl or xe2x80x94CzfaH2zfaxe2x80x94R(180),
zfa is zero or 1,
R(180) is (C5-C7)-cycloalkyl or phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methoxy or methyl,
xe2x80x83or
R(177) and R(178) are together 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl,
R(179) is defined as R(177),
R(104) is hydrogen, CF3 (C1-C8)-alkyl or xe2x80x94CzalH2zalR(118a),
zal is zero or 1,
R(118a) is (C3-C6)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(119a)R(119b),
R(119a) and R(119b) being hydrogen or CH3,
or
R(104) is quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl which are linked via C or N and which are unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino,
or
R(104) is R(110a)xe2x80x94SO2 or R(112a)R(113a)Nxe2x80x94SO2xe2x80x94,
R(110a) is (C1-C4)-alkyl or CF3,
R(112a) is hydrogen, (C1-C4)-alkyl, CF3 or xe2x80x94CzaH2zaxe2x80x94R(115a),
za is zero or 1,
R(115a) is phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(116a)R(117a),
R(116a) and R(117a) being hydrogen or CH3,
R(113a) is hydrogen or CH3,
or
R(104) is xe2x80x94Cxe2x89xa1CR(193),
R(193) is phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(194)R(195),
R(194) and R(195) being hydrogen or CH3,
R(105) is hydrogen,
and also the pharmaceutically tolerated salts thereof.
Dibenzoylguanidines of the formula Ia
are likewise preferred
in which:
R(1), R(5), R(6) and R(10) are, independently of each other, 
xe2x80x83hydrogen, F, Cl, (C1-C3)-alkyl, xe2x80x94OR(11), CrF2r+1 or xe2x80x94NR(11)R(12),
R(11) and R(12) are, independently, hydrogen or (C1-C3)-alkyl,
r is from 1 to 4,
R(2), R(4), R(7) and R(9) are, independently of each other, hydrogen, F, Cl, Br, I, xe2x80x94Cxe2x89xa1N, Xoxe2x80x94(CH2)pxe2x80x94(CF2)qxe2x80x94CF3, R(13)xe2x80x94SOm, R(14)R(15)Nxe2x80x94COxe2x80x94, R(16)xe2x80x94COxe2x80x94 or R(17)R(18)Nxe2x80x94SO2xe2x80x94,
X is oxygen, S or NR(19),
m is zero, 1 or 2,
o is zero or 1,
p is zero, 1 or 2,
q is zero, 1, 2, 3, 4, 5 or 6,
R(13), R(14), R(16) and R(17) are, independently, (C1-C8)-alkyl, (C3-C6)-alkenyl, xe2x80x94CnH2nxe2x80x94R(20) or CF3,
n is zero, 1, 2, 3 or 4,
R(19) is hydrogen or (C1-C3)-alkyl,
R(20) is (C3-C7)-cycloalkyl or phenyl which is not substituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(21)R(22) with R(21) and R(22) being H or (C1-C4)-alkyl,
xe2x80x83where R(14), R(16) and R(17) also have the meaning of H,
R(15) and R(18) are, independently, hydrogen or (C1-C4)-alkyl, where R(14) and R(15) and also R(17) and R(18) can together be 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl,
or
R(2), R(4), R(7) and R(9) are, independently of each other, (C1-C8)-alkyl or xe2x80x94CalH2alR(84),
al is zero, 1 or 2,
R(84) is (C3-C8)-cycloalkyl or phenyl which is not substituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(85)R(86), with R(85) and R(86) being hydrogen or CH3; or
R(2), R(4), R(7) and R(9) are, independently of each other, (C1-C9)-heteroaryl which is linked via C or N and which is unsubstituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino or dimethylamino; or
R(2), R(4), R(7) and R(9)are, independently of each other, xe2x80x94Cxe2x89xa1CR(93),
R(93) is phenyl which is unsubstituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(94)R(95), with R(94) and R(95) being hydrogen or CH3;
R(3) and R(8) are, independently of each other, defined as R(2), or are 
Y is oxygen, xe2x80x94Sxe2x80x94 or xe2x80x94NR(83)xe2x80x94,
h, ad and ah are, independently, zero or 1,
i, j, k, ae, af, ag, ao, ap and ak are, independently, zero, 1, 2, 3 or 4,
xe2x80x83where, however, in each case, h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero and
ah, ao and ak are not simultaneously zero,
R(23), R(24), R(25) and R(83) are, independently, hydrogen or (C1-C3)-alkyl,
or
R(3) and R(8) are, independently of each other, hydrogen, F, Cl, Br, I, CN, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8-alkenyl or xe2x80x94CgH2gR(26),
g is zero, 1, 2, 3 or 4,
R(26) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(27)R(28), with R(27) and R(28) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or
R(3) and R(8) are, independently of each other, SR(29), xe2x80x94OR(30), xe2x80x94NR(31)R(32) or xe2x80x94CR(33)R(34)R(35);
R(29), R(30), R(31) and R(33) are, independently, xe2x80x94CaH2a-(C1-C9)-heteroaryl which is unsubstituted or substituted by 1-3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino or dimethylamino,
a is zero, 1 or 2,
R(32), R(34) and R(35) are, independently of each other, defined as R(29), or hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or
R(3) and R(8) are, independently of each other, 
R(96), R(97) and R(98) are, independently, (C1-C9)-heteroaryl which is linked via C or N and which is unsubstituted or is substituted by 1 to 3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino, dimethylamino or benzyl,
W is oxygen, S or NR(99)xe2x80x94,
R(99) is hydrogen or (C1-C4)-alkyl,
or
R(3) and R(8) are, independently of each other,
R(72)xe2x80x94SOm or R(73)R(74)Nxe2x80x94SO2xe2x80x94,
m is 1 or 2,
R(72) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or xe2x80x94CsH2sxe2x80x94R(75),
s is zero, 1, 2, 3 or 4,
R(75) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(76)R(77), with R(76) and R(77) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(73) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or xe2x80x94CwH2wxe2x80x94R(78),
w is zero, 1, 2, 3 or 4,
R(78) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(79)R(80), with R(79) and R(80) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
R(74) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
xe2x80x83where R(73) and R(74) can together be 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl; or
R(3) and R(8) are, independently of each other, R(39)Xxe2x80x94,
X is oxygen, S, NR(40), (Dxe2x95x90O)Axe2x80x94 or
NR(41)Cxe2x95x90MN(*)R(42)xe2x80x94, with
M is oxygen or S,
A is oxygen or NR(43), and
D is C or SO,
R(39) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1 or xe2x80x94CxH2xxe2x80x94R(44),
b is zero or 1,
d is 1, 2, 3, 4, 5, 6 or 7,
x is zero, 1, 2, 3 or 4,
R(44) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(45)R(46); with R(45) and R(46) being hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(40), R(41) and R(43) are, independently, hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
R(42) is defined as R(39), where
R(39) and R(40), or R(39) and R(41), respectively, can together be 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl, where
A and N(*) are bonded to the phenyl nucleus of the benzoylguanidine parent substance; or
R(3) and R(8) are, independently of each other, xe2x80x94SR(47), xe2x80x94OR(48), xe2x80x94NHR(49), xe2x80x94NR(50)R(51), xe2x80x94CHR(52)R(53), 
R(47), R(48), R(49), R(50) and R(52) are identical or different and are xe2x80x94(CH2)yxe2x80x94(CHOH)zxe2x80x94(CH2)aaxe2x80x94(CH2OH)txe2x80x94R(64) or (CH2)abxe2x80x94Oxe2x80x94(CH2xe2x80x94CH2O)acxe2x80x94R(65),
R(64) and R(65) are hydrogen or methyl,
u=1, 2, 3 or 4,
v=zero, 1, 2, 3 or 4,
y, z and aa are identical or different and are zero, 1, 2, 3 or 4,
t=1, 2, 3 or 4,
R(51), R(53), R(54) and R(55) are identical or different and are hydrogen or (C1-C6)-alkyl, or
R(52) and R(53), or R(54) and R(55), respectively, are, together with the carbon atom carrying them, a (C3-C8)-cycloalkyl;
R(63) is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or xe2x80x94CeH2exe2x80x94R(81),
e is zero, 1, 2, 3 or 4,
R(56), R(57) and R(81) are, independently, phenyl which is unsubstituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(82)R(66) with R(82) and R(66) being H or (C1-C4)-alkyl, or
R(56), R(57) and R(81) are, independently, (C1-C9)-heteroaryl which is unsubstituted or is substituted as phenyl;
R(58), R(59), R(60), R(61) and R(62) are hydrogen or methyl, or
R(3) and R(8) are, independently of each other,
R(67)xe2x80x94NHxe2x80x94SO2xe2x80x94,
R(67) is R(68)R(69)Nxe2x80x94(Cxe2x95x90Yxe2x80x2)xe2x80x94,
Yxe2x80x2 is oxygen, S or Nxe2x80x94R(70),
R(68) and R(69) are identical or different and are hydrogen, (C1-C8)-alkyl, (C3-C6)-alkenyl or xe2x80x94CfH2fxe2x80x94R(71),
f is zero, 1, 2, 3 or 4,
R(71) is (C5-C7)-cycloalkyl or phenyl which is unsubstituted or substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methoxy or (C1-C4)-alkyl, or
R(68) and R(69) together form 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl, where R(70) is defined as R(68) or is amidine;
and also pharmaceutically tolerated salts thereof,
where, however, compounds are excepted in which the radicals R(1) to R(10) are combined as follows:
Compounds of the formula Ia are likewise particularly preferred in which:
R(5)=R(6)=hydrogen, the remaining residues are defined as above, and
R(1)=R(10)
R(2)=R(9)
R(3)=R(8)
R(4)=R(7).
Compounds of the formula Ia are likewise very particularly preferred in which:
R(1)=R(10) =hydrogen, F, Cl, CH3, OH, NH2 and CF3,
R(2)=R(9) =hydrogen, F, Cl, Br, xe2x80x94Cxe2x89xa1N, xe2x80x94CqF2qCF3, R(13)xe2x80x94SO2, R(14)R(15) Nxe2x80x94COxe2x80x94, R(16)xe2x80x94COxe2x80x94 or R(17)R(18) Nxe2x80x94SO2xe2x80x94,
R(13), R(14), R(16) and R(17) are, independently, (C1-C8)xe2x80x94alkyl, (C3-C4)xe2x80x94alkenyl, xe2x80x94CnH2nxe2x80x94R(20) or CF3,
n is zero or 1,
q is zero, 1, 2, 3, 4 or 5,
R(20) is (C3-C6)xe2x80x94cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(21)R(22),
R(21) and R(22) being hydrogen or methyl, where R(14), R(16) and R(17) also have the meaning of hydrogen,
R(15) and R(18) are, independently, hydrogen or methyl,
R(3) and R(8) are, independently of each other, 
Y is oxygen, S or xe2x80x94NR(83),
R(23), R(24), R(25) and R(83) are, independently, hydrogen or methyl,
h, ad and ah are, independently, zero or 1,
i, k, ae, ag, ao and ak are, independently, zero, 1, 2 or 3,
j, af and ap are, independently, zero or 1,
where, however, in each case, h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero and
ah, ao and ak are not simultaneously zero,
or
R(3)=R(8) =hydrogen, F, Cl, Br, CN, (C1-C8)xe2x80x94alkyl, CF3, (C3-C8)xe2x80x94alkenyl or xe2x80x94CgH2gR(26),
g is zero, 1 or 2,
R(26) is (C3-C6)xe2x80x94cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(27)R(28), with R(27) and R(28) being H or CH3;
or
R(3)=R(8) =(C1-C9)xe2x80x94heteroaryl, which is linked via C or N and which is unsubstituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino or dimethylamino;
or
R(3) and R(8) are independently of each other, 
R(96), R(97) and R(98) are, independently, pyrrolyl, imidazolyl, pyrazolyl or pyridyl which in each case is unsubstituted or substituted by 1 to 2 radicals from the group consisting of F, Cl, CF3, CH3, methoxy, dimethylamino or benzyl,
W is oxygen, xe2x80x94Sxe2x80x94 or NR(99)xe2x80x94,
R(99) being hydrogen or methyl,
or
R(3)=R(8) =xe2x80x94SR(29), xe2x80x94OR(30), xe2x80x94NR(31)R(32) or xe2x80x94CR(33)R(34)R(35),
R(29), R(30), R(31) and R(33) are, independently of each other, xe2x80x94CaH2axe2x80x94(C1-C9)xe2x80x94heteroaryl which is unsubstituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino or dimethylamino.
a is zero or 1,
R(32), R(34) and R(35) are, independently of each other, hydrogen or CH3;
or
R(3)=R(8) =R(72)xe2x80x94SO2 or R(73)R(74)Nxe2x80x94SO2xe2x80x94,
R(72) is (C1-C4)xe2x80x94alkyl, CF3, (C3-C4)xe2x80x94alkenyl or xe2x80x94CsH2sxe2x80x94R(75),
s is zero or 1,
R(75) is (C3-C6)xe2x80x94cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(76)R(77); with R(76) and R(77) being hydrogen or CH3,
R(73) is hydrogen, (C1-C4)xe2x80x94alkyl, CF3, (C3-C4)xe2x80x94alkenyl or
xe2x80x94CwH2wxe2x80x94R(78),
w is zero or 1,
R(78) is (C3-C6)xe2x80x94cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(79)R(80), with R(79) and R(80) being hydrogen or CH3,
R(74) is hydrogen or CH3, where R(73) and R(74) can together be 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl;
or
R(3)=R(8) =R(39)Xxe2x80x94,
X is oxygen, S, NR(40), (C=O)Axe2x80x94, NR(41)C=MN(*)Rxe2x80x94(42)xe2x80x94,
M is oxygen, and
A is oxygen or NR(43),
R(39) is (C1-C6)xe2x80x94alkyl, (C3-C4)xe2x80x94alkenyl, (CH2)bCdF2d+1 or xe2x80x94CxH2xxe2x80x94R(44),
b is zero or 1,
d is 1-7,
x is zero or 1, R(44) is (C3-C6)xe2x80x94cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(45)R(46), with R(45) and R(46) being hydrogen or CH3,
R(41) is hydrogen or (C1-C4)xe2x80x94alkyl,
R(42) is defined as R(39), where
R(39) and R(40), or R(39) and R(41), respectively, can together be 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or N-benzyl, where A and N(*) are bonded to the phenyl nucleus of the benzoylguanidine parent substance;
or
R(3) and R(8) are xe2x80x94SR(47), xe2x80x94OR(48), xe2x80x94NHR(49), xe2x80x94NR(50)R(51), xe2x80x94CHR(52)R(53), 
(R(47), R(48), R(49), R(50) and R(52) are identical or different and are xe2x80x94(CH2)yxe2x80x94(CHOH)zxe2x80x94(CH2)aaxe2x80x94(CH2OH)txe2x80x94R(64) or xe2x80x94(CH2)abxe2x80x94Oxe2x80x94(CH2xe2x80x94CH2O)acxe2x80x94R(65), with R(64) and R(65) being hydrogen or methyl,
u is 1 or 2,
v is zero, 1 or 2,
y, z, aa, ab and ac are identical or different and are zero, 1 or 2,
t is 1, 2 or 3,
R(51), R(53), R(54) and R(55) are identical or different and are hydrogen or methyl, or
R(52) and R(53), or R(54) and R(55), respectively, are, together with the carbon atom carrying them, a (C3-C6)xe2x80x94cycloalkyl,
R(63) is hydrogen, (C1-C4)xe2x80x94alkyl, (C3-C6)xe2x80x94cycloalkyl or xe2x80x94CeH2exe2x80x94R(81),
e is zero, 1 or 2,
R(56), R(57) and R(81) are, independently of each other, phenyl which is unsubstituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(65)R(66) with R(65) and R(66) being hydrogen or CH3; or
R(56), R(57) and R(81) are, independently of each other, (C1-C9)xe2x80x94heteroaryl which is unsubstituted or is substituted as phenyl;
R(58), R(59), R(60), R(61) and R(62) are hydrogen or methyl,
or
R(3) and R(8) are R(67)xe2x80x94NHxe2x80x94SO2xe2x80x94,
R(67) is R(68)R(69)Nxe2x80x94(C=Yxe2x80x2)xe2x80x94,
Yxe2x80x2 is oxygen, S or Nxe2x80x94R(70), R(68) and R(69) are identical or different and are hydrogen, (C1-C4)xe2x80x94alkyl, (C3-C4)xe2x80x94alkenyl or xe2x80x94CfH2fxe2x80x94R(71),
f is zero or 1,
R(71) is (C5-C7)xe2x80x94cycloalkyl or phenyl which is unsubstituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methoxy or methyl, or
R(68) and R(69) together form 4 or 5 methylene groups of which one CH2 group can be replaced by oxygen, S, NH, Nxe2x80x94CH3 or Nxe2x80x94benzyl,
R(70) is defined as R(68);
R(4)=R(7) =(C1-C8)xe2x80x94alkyl, xe2x80x94CalH2alR(84) or CF3,
al is zero or 1,
R(84) is (C3-C6)xe2x80x94cycloalkyl or phenyl which is not substituted or is unsubstituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(85)R(86), with R(85) and R(86) being hydrogen or CH3,
or
R(4)=R(7) =quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl which are linked via C or N and which are unsubstituted or are substituted by 1-2 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino or dimethylamino,
or
R(4)=R(7) =R(87)xe2x80x94SOam or R(88)R(89)Nxe2x80x94SO2xe2x80x94,
am is 2,
R(87) is (C1-C4)xe2x80x94alkyl or CF3.
R(88) is hydrogen, (C1-C4)xe2x80x94alkyl, CF3 or xe2x80x94CanH2anxe2x80x94
R(90),
an is zero or 1,
R(90) is phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(90)R(91), with R(90) and R(91) being hydrogen or CH3,
R(89) is hydrogen or CH3,
or
R(4)=R(7) =xe2x80x94Cxe2x89xa1CR(93),
R(93) is phenyl which is unsubstituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF3, methyl, methoxy or NR(94)R(95) with R(94) and R(95) being hydrogen or CH3;
R(5)=R(6) =hydrogen,
and also the pharmaceutically acceptable salts thereof.
(C1-C9)xe2x80x94Heteroaryl is, in particular, understood to mean radicals which are derived from phenyl or naphthyl and in which one or more CH groups are replaced by N, and/or in which at least two adjacent CH groups are replaced by S, NH or O (with the formation of a five-membered aromatic ring). In addition, one or both atoms of the condensation site of bicyclic radicals can also be N atoms (as in indolizinyl).
Heteroaryl is considered, in particular, to be furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl.
Should one of the substituents R(1) to R(198) contain one or more centers of asymmetry, these centers can then be in either the S or the R configuration. The compounds can be present as optical isomers, as diastereomers, as racemates, or as mixtures thereof.
The designated alkyl and perfluoroalkyl radicals can be present either in the straight-chain or the branched form.
The invention relates furthermore to a process for preparing the compounds I, wherein either
two equivalents of the compounds of the formula II are reacted with one equivalent of guanidine 
where X(1) and X(2) have the given meaning and L is a leaving group which can readily be substituted nucleophilically, or
a compound of the formula IIa 
is reacted with a compound of the formula III 
with the participation of a base, for example K2CO3, NaOH or triethylamine, where X(1) and X(2) have the given meaning and L is a leaving group which can readily be substituted nucleophilically.
The activated acid derivatives of the formula II, in which L is an alkoxy, preferably a methoxy, group, a phenoxy group, a phenylthio, methylthio or 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained, in a manner known per se, from the underlying carbonyl chlorides (formula II, L=Cl), which, for their part, can be prepared, once again in a manner known per se, from the underlying carboxylic acids (formula II, L=OH), for example using thionyl chloride.
In addition to the carbonyl chlorides of the formula II (L=Cl), other activated acid derivatives of the formula II can also be prepared, in a manner known per se, directly from the underlying benzoic acid derivatives (formula II, L=OH) as can, for example, the methyl esters of the formula II with L=OCH3 by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole [L=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II with Clxe2x80x94COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, in addition to which there is also the activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or with Oxe2x80x94[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (xe2x80x9cTOTUxe2x80x9d) [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A series of suitable methods for preparing activated carboxylic acid derivatives of the formula II is given, with citation of the source literature, on p. 350 in J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985).
An activated carboxylic acid derivative of the formula II is reacted with guanidine, in a manner known per se, in a protic or aprotic polar, but nevertheless inert, organic solvent. In this context, methanol, isopropanol or THF, at a temperature of from 20xc2x0 C. up to the boiling temperature of these solvents, have proved of value when reacting the methylbenzoates (II, L=OMe) with guanidine. Most of the reactions of compounds II with salt-free guanidine were advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane or dioxane. However, water can also be used, while employing a base such as, for example, NaOH, as the solvent, when reacting II with guanidine.
When L denotes Cl, the reaction is advantageously carried out with the addition of an acid-capturing agent, for example in the form of excess guanidine, for binding and thus removing the hydrohalic acid.
Some of the underlying benzoic acid derivatives of the formula II are known and are described in the literature. The unknown compounds of the formula II may be prepared by methods which are known from the literature. The introduction of some of the substituents is achieved by the methods, which are known from the literature, of palladium-mediated cross-coupling or aryl halides or aryl triflates with, for example, organostannanes, organoboronic acids, organoboranes, or organocopper or organozinc compounds, or terminal alkynes. The resulting benzoic acids are converted into activated benzoic acid derivatives of the formula II by one of the above-described process variants. The compounds of the formula II are either converted directly into the compounds of the formula I according to the invention or transformed initially with guanidine into compounds of the formula III which, following isolation, are converted into the compounds of the formula I according to the invention by reaction with a further compound of the formula II.
In general, dialkanoyl-substituted guanidines of the formula I are weak bases and can bind acid with the formation of salts. Suitable acid addition salts are the salts of all pharmacologically tolerated acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.
The compounds I are dialkanoyl-substituted guanidines which both directly inhibit the cellular sodium/proton exchanger (Na+/H+exchanger of Na+/H+antiporter) and also lose one of their acyl radicals in vivo, with a half life of between 1 minute and 10 hours, and thus, in turn, liberate monoacylguanidines, which are efficient inhibitors of the cellular sodium/proton exchanger. Compounds of the formula I are therefore potent inhibitors of the cellular sodium/proton exchanger and lead to an improvement in the kinetics of the underlying monoacylguanidines. Over and above this, they give rise, owing to their lipophilic nature, to higher concentrations in the CNS of active compounds in the form of dialkanoylguanidines and monoacylguanidines than are achieved using the monoacylguanidines.
As a consequence of their pharmacological properties, the compounds are outstandingly suitable for use as anti-arrhythmic pharmaceuticals possessing a cardioprotective component for the prophylaxis and treatment of infarction and for the treatment of angina pectoris, in connection with which they also inhibit or strongly reduce, in a preventive manner, the pathophysiological processes associated with the genesis of ischemically induced damage, in particular associated with the elicitation of ischemically induced cardiac arrhythmias. On account of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can, as a consequence of inhibiting the cellular Na+/H+exchange mechanism, be used as pharmaceuticals for treating all acute or chronic damage elicited by ischemia, or diseases induced primarily or secondarily thereby. This is the case with regard to their use as pharmaceuticals for surgical interventions, for example in organ transplantations, where the compounds can be used both for protecting the organs in the donor prior to and during removal, for protecting organs which have been removed, for example when they are being treated with or stored in physiological bathing fluids, and when transferring the organs into the recipient. The compounds are likewise valuable protective pharmaceuticals to be used when carrying out angioplastic surgical interventions, for example on the heart or on peripheral vessels. In conformity with their ability to protect against ischemically induced damage, the compounds are also suitable for use as pharmaceuticals for treating ischemias of the nervous system, in particular of the CNS, in connection with which they are suitable, for example, for treating stroke or cerebral edema. Over and above this, the compounds of the formula I according to the invention are also suitable for use in the treatment of forms of shock, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shock.
In addition to this, the compounds of the formula I according to the invention are notable for their strong inhibitory effect on the proliferation of cells, for example, the proliferation of fibroblast cells and the proliferation of the smooth muscle cells of the blood vessels. For this reason, the compounds of the formula I are valuable therapeutic agents for use in diseases in which cell proliferation represents a primary or secondary cause and may, therefore, be used as anti-atherosclerotic agents, and as agents against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and against organ hypertrophies or hyperplasias, in particular hyperplasia or hypertrophy of the prostate.
The compounds according to the invention are efficient inhibitors of the cellular sodium/proton antiporter (Na30/H30 exchanger), which, in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.), is also elevated in those cells which are readily accessible to measurement, such as, for example, erythrocytes, thrombocytes or leucocytes. The compounds according to the invention therefore represent outstanding and simple scientific tools, for example in their use as diagnostic aids for defining and differentiating particular forms of hypertension and also of atherosclerosis, diabetes, proliferative diseases, etc. In addition to this, the compounds of the formula I can suitably be used in preventive therapy for preventing the genesis of high blood pressure, for example of essential hypertension.
In this context, pharmaceuticals which contain a compound I may be administered orally, parenterally, intravenously or rectally, or by inhalation, the preferred route of administration depending on the given features of the disease. In this context, the compounds I may be used either alone or together with pharmaceutical auxiliary substances, both in veterinary and in human medicine.
Owing to his specialist knowledge, the person skilled in the art is familiar with those auxiliary substances which are suitable for the desired pharmaceutical formulation. Antioxidants, dispersants, emulsifiers, defoamers, taste corrigents, preservatives, solubilizers or dyes, for example, can be used in addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active compound excipients.
For a form for oral use, the active compounds are mixed with the additives, such as carrier substances, stabilizers or inert diluents, which are suitable for the purpose, and brought by the customary methods into the forms, such as tablets, coated tablets, hard gelatin capsules, or aqueous, alcoholic or oily solutions, which are suitable for administration. Gum arabic, magnesium hydroxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch, can, for example, be used as inert excipients. In this context, the preparation can be effected either as a dry granulate or as a wet granulate. Vegetable or animal oils, for example, such as sunflower oil or cod-liver oil, are suitable for use as oily excipients or as solvents.
For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired using the substances, such as solubilizers, emulsifiers or other auxiliary substances, which are customary for the purpose. Examples of suitable solvents are: water, physiological sodium chloride solution or alcohols, for example ethanol, propanol or glycerol, as well as sugar solutions, such as glucose or mannitol solutions, or else a mixture of the different solvents mentioned.
Solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically harmless solvent, such as, in particular, ethanol or water, or in a mixture of such solvents, represent examples of suitable pharmaceutical formulations for administration in the form of aerosols or sprays.
As required, the formulation can also contain additional pharmaceutical auxiliary substances such as surfactants, emulsifiers and stabilizers, as well as a propellent gas. Such a preparation customarily contains the active compound in a concentration of from about 0.1 to 10, in particular of from about 0.3 to 3, % by weight.
The dosage of the active compound of the formula I to be administered, and the frequency of administration, depend on the strength and duration of the effect of the compounds used; additionally also on the nature and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammalian subject to be treated.
On average, the daily dose of a compound of the formula I is, for a patient of approximately 75 kg in weight, at least 0.001 mg/kg, preferably 0.01 mg/kg, up to at most 10 mg/kg, preferably 1 mg/kg, of body weight. In acute manifestations of the disease, for example immediately after suffering a cardiac infarction, even greater and, in particular, more frequent dosages may also be necessary, for example up to 4 individual doses per day. In the case of i.v. use in particular, for example in an infarction patient in intensive care, up to 200 mg per day may be necessary.
List of abbreviations:
Experimental section
General instructions for preparing monoacylguanidines (III)
Variant A: from carboxylic acids (II, L=OH)
1.0 eq. of the carboxylic acid derivative of the formula II is dissolved or suspended in anhydrous THF (5 ml/mmol), and 1.1 eq. of carbonyldiimidazole are then added. After the mixture has been stirred at RT for 2 hours, 5.0 eq. of guanidine are introduced into the reaction solution. After the mixture has been stirred overnight, the THF is distilled off under reduced pressure in a rotary evaporator and water is added to the residue, which is adjusted to from pH 6 to 7 with 2N HCl; the corresponding monoacylguanidine (formula III) is then filtered off. The monoacylguanidines obtained in this way can be converted into the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically tolerated acids.
General instructions for preparing monoacylguanidines (III)
Variant B: from alkyl carboxylates (II, L=O-alkyl)
1.0 eq. of the alkyl carboxylate of the formula II and also 5.0 eq. of guanidine (free base) are dissolved in isopropanol or suspended in THF and boiled under reflux until the reaction is complete (monitoring by thin layer chromatography) (typical reaction time, from 2 to 5 h). The solvent is distilled off under reduced pressure in a rotary evaporator and the residue is taken up in EA and washed 3 xc3x97 with a solution of NaHCO3. Drying takes place over Na2SO4, after which the solvent is distilled off in vacuo and the residue is chromatographed on silica gel using a suitable eluent, for example EA/MeOH 5:1. (Salt formation, compare variant A)
General instructions for preparing dialkanoylguanidines (I)
Variant F: from carboxylic acids (II, L=OH)
2.0 eq. of the carboxylic acid derivative of the formula II are dissolved or suspended in anhydrous THF (5ml/mmol), and 2.2 eq. of carbonyldiimidazole are then added. After the mixture has been stirred at RT for 2 hours, 1.0 eq. of guanidine is introduced into the reaction solution. After the mixture has been stirred overnight, the THF is distilled off under reduced pressure in a rotary evaporator, and water is added to the residue, which is adjusted to from pH 6 to 7 with 2N HCl; the corresponding dialkanoylguanidine (formula I) is then filtered off. The monoacylguanidines obtained in this way can be converted into the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically tolerated acids.
General instructions for preparing dialkanoylguanidines (I)
Variant G: from carboxylic acid esters (II, L=O-alkyl)
2.0 eq. of the alkyl carboxylate of the formula II and also 1.0 eq. of guanidine (free base) are dissolved in isopropanol or suspended in THF and boiled under reflux until the reaction is complete (monitoring by thin layer chromatography) (typical reaction time, from 2 to 5 h). The solvent is distilled off under reduced pressure in a rotary evaporator and the residue is taken up in EA and washed 3 xc3x97 with a solution of NaHCO3. Drying takes place over Na2SO4, after which the solvent is distilled off in vacuo and the residue is chromatographed on silica gel using a suitable eluent, e.g. EA/MeOH 5:1. (Salt formation, compare variant A)
General instructions for preparing dialkanoylguanidines (I)
Variant K: from monoacylguanidines (III) and a carboxylic acid derivative of the formula II (for example, a carboxylic acid ester or activated carboxylic acid)
1.0 eq. of the monoacylguanidine of the formula III (free base) and also 1.0 eq. of the carboxylic acid derivative of the formula II (for the preparation of an activated carboxylic acid, compare variant A) are dissolved or suspended, respectively, in isopropanol or in THF and the mixture is stirred at an appropriate temperature (RT to reflux) until the reaction is complete (monitoring by thin layer chromatography). The solvent is distilled off under reduced pressure in a rotary evaporator and the residue is taken up in EA and washed 3 xc3x97 with a solution of NaHCO3. Drying over takes place Na2SO4, after which the solvent is distilled off in vacuo and the residue is chromatographed on silica gel using a suitable eluent, e.g. EA/MeOH 10:1. (Salt formation, compare variant A)